Atherosclerosis is a chronic inflammatory process of the vascular endothelium that leads to cardiovascular disease. Generation of oxidized form of LDL (oxLDL) and its uptake by macrophages is an early event in the atherosclerosis. OxLDL also induces an autoimmune response as evidenced by the presence of antibody (IgG) against oxLDL and oxLDL-immune complex (oxLDL-IC) in atherosclerotic lesions in patients and animal model. The titer of autoantibodies against oxLDL is correlated with the progression of atherosclerosis in humans and in the hyperlipidemic mouse model. Therefore, oxLDL-IC could be involved in the inflammatory processes leading to the initiation and progression of atherosclerosis. We have shown that human monocytes adhere to oxLDL-IC coated endothelial cells in vitro and release inflammatory cytokines. This interaction is mediated through a group of cellular receptors called Fc gamma receptors (Fc?R), which bind immune complexes and play a major role in IC-mediated tissue injury in chronic inflammatory disease involving autoantibodies. Interaction of oxLDL-IC with Fc?Rs containing activation motif could initiate an inflammatory response while interaction with Fc?R containing the inhibitory receptor will dampen the inflammatory process. However, the role of Fc?R in initiation and progression of atherosclerosis is not known. We have generated double knock out mice lacking the activating or inhibitory Fc?R, in atherosclerosis prone apoE-/- mice, providing us tools to study the role of Fc?R during atherosclerosis. We have also observed that in addition to its interaction with IC, mouse CD16, a Fc?R can bind oxLDL directly and could have scavenger receptor like activity. Therefore in this proposal we will, (i) determine the role of activating Fc?R during atherosclerosis in vivo, (ii) delineate molecular mechanisms contributing to the attenuated lesions in the activating Fc?R deficient mice, (iii) determine the role of inhibitory Fc?R during atherosclerosis in vivo, and (iv) characterize the SR-like activity of mouse CD16 and determine its functional implications. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the progression of atherosclerosis. Further, Our findings would allow for future development of therapeutics to block Fc?R-mediated inflammation with the goal of blocking or preventing the progression of atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis remains the leading cause of death in the USA and other Western countries. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the lesion development during atherosclerosis. Further, it could allow for designing therapeutics by inhibiting atherogenesis via targeting activating and/or inhibitory Fc?Rs.